Cell type-specific functions of HMGB1 in necroinflammation of the kidney

点击翻译按钮获取中文摘要

The rsults of the previous project document that extracellular histones and neutrophil extracellular traps have important roles in renal necroinflammaiton of acute postischemic kidney injury. But the cell type-specific sources of extracellular histones could not be studied, because cell type-specific depletion of histones is technically not feasible. Therefore, we focus here on the nucleoprotein high mobility group box (Hmgb)-1, which elicits similar DAMP effects as histones in the extracellular space. Because Hmgb1 is dispensible in the nucleus Hmgb1-flox mice have become available. We will generate mouse lines with selective depletion of Hmgb1 in tubular epithelial cells, resident immune cells, and infiltrating immune cells. After induction of a postischemic tubular necrosis with acute kidney injury the contribution of Hmgb1 from each cell type can be studied. It will be necessary to distingiush intracellular from extracellular functions of Hmgb1. Based on our preliminary work this project will focus in particular on the long-term outcomes of acute kidney injury, i.e. kidney regeneration and tumorigenesis, which are both tightly connected after acute kidney injury. We will study the effects of pharmacological inhibition of Hmgb1 as well as the cell type-specific deficiency of Hmgb1 on these outcomes. We expect a bette runderstanding of renal necroinflammation and its impact on the long-term outcomes after acute kidney injury.